rs1057518748

Positions:

• chr5-110761530-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_138773.4(SLC25A46):​c.1005A>T​(p.Glu335Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC25A46 NM_138773.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.22

Genes affected

SLC25A46 (HGNC:25198): (solute carrier family 25 member 46) This gene encodes a mitochondrial solute carrier protein family member. It functions in promoting mitochondrial fission, and prevents the formation of hyperfilamentous mitochondria. Mutation of this gene results in neuropathy and optic atrophy. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_138773.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-110761530-A-T is Pathogenic according to our data. Variant chr5-110761530-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 372239.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC25A46	NM_138773.4	c.1005A>T	p.Glu335Asp	missense_variant	8/8	ENST00000355943.8
SLC25A46	NM_001303249.3	c.762A>T	p.Glu254Asp	missense_variant	8/8
SLC25A46	NM_001303250.3	c.732A>T	p.Glu244Asp	missense_variant	8/8
SLC25A46	NR_138151.2	n.1244A>T		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC25A46	ENST00000355943.8	c.1005A>T	p.Glu335Asp	missense_variant	8/8	1	NM_138773.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neuropathy, hereditary motor and sensory, type 6B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;.;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Benign	-0.67	T
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.015	D;D;T;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.88
MutPred		0.58		.;Gain of relative solvent accessibility (P = 0.0479);.;.;.;
MVP		0.46
MPC		0.32
ClinPred		0.94	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057518748; hg19: chr5-110097230;